Genetic Variant NM_002807.4:c.1072-3C>T (chr2-231078656-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002807.4(PSMD1):c.1072-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,597,164 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 22 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 12 hom. )

Consequence

PSMD1
NM_002807.4 splice_region, intron

Scores

Splicing: ADA: 0.0001436

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.66

Publications

2 publications found

Variant links:

Genes affected

PSMD1 (HGNC:9554): (proteasome 26S subunit, non-ATPase 1) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes the largest non-ATPase subunit of the 19S regulator lid, which is responsible for substrate recognition and binding. There is evidence that this proteasome and its subunits interact with viral proteins, including those of coronaviruses. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Aug 2020]

PSMD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-231078656-C-T is Benign according to our data. Variant chr2-231078656-C-T is described in ClinVar as Benign. ClinVar VariationId is 789572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00732 (1114/152258) while in subpopulation AFR AF = 0.0258 (1071/41546). AF 95% confidence interval is 0.0245. There are 22 homozygotes in GnomAd4. There are 549 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1114 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002807.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PSMD1	NM_002807.4	MANE Select	c.1072-3C>T	splice_region intron	N/A	NP_002798.2
PSMD1	NM_001191037.2		c.1072-3C>T	splice_region intron	N/A	NP_001177966.1	Q99460-2
PSMD1	NR_034059.2		n.1061-3C>T	splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PSMD1	ENST00000308696.11	TSL:1 MANE Select	c.1072-3C>T	splice_region intron	N/A	ENSP00000309474.6	Q99460-1
PSMD1	ENST00000431051.6	TSL:1	n.*755-3C>T	splice_region intron	N/A	ENSP00000400483.1	F8WCE3
PSMD1	ENST00000971494.1		c.1072-3C>T	splice_region intron	N/A	ENSP00000641553.1

Frequencies

GnomAD3 genomes

AF:

0.00730

AC:

1111

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00200

AC:

476

AN:

237522

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0270

Gnomad AMR exome

AF:

0.00135

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000730

Gnomad OTH exome

AF:

0.000695

GnomAD4 exome

AF:

0.000734

AC:

1061

AN:

1444906

Hom.:

Cov.:

AF XY:

0.000653

AC XY:

469

AN XY:

718234

show subpopulations

African (AFR)

AF:

0.0258

AC:

837

AN:

32426

American (AMR)

AF:

0.00160

AC:

AN:

41882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

38956

South Asian (SAS)

AF:

0.0000366

AC:

AN:

81924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52990

Middle Eastern (MID)

AF:

0.00315

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

1105598

Other (OTH)

AF:

0.00172

AC:

103

AN:

59710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00732

AC:

1114

AN:

152258

Hom.:

Cov.:

AF XY:

0.00737

AC XY:

549

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0258

AC:

1071

AN:

41546

American (AMR)

AF:

0.00163

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68020

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00377

Hom.:

Bravo

AF:

0.00826

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.6

(source)

DANN

Benign

0.58

PhyloP100

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over